PROJECT SUMMARY Anthracyclines are common antineoplastic agents of known cardiotoxicity. While early detection and improved therapeutic approaches have increased the odds of survival for cancer patients, adverse cardiovascular effects in cancer survivors are often discovered upon occurrence of clinical symptoms, when myocardial injury cannot be reversed. Given the increasing population of cancer survivors, there is an urgent need to identify a set of reliable metrics that can estimate the cardiovascular risk in patients treated with anthracyclines. Motivated by reports of aortic stiffening following anthracycline treatment, and recalling that aortic stiffening is an independent risk factor for cardiovascular disease, this proposal intends to evaluate the use of aortic stiffness as an early predictor of cardiovascular dysfunction following anthracycline chemotherapy. To address this question, our team brings together expertise in cardiac magnetic resonance (MR) imaging, experimental and computational vascular mechanics, and clinical cardio-oncology. Research activities will focus on a mouse model of anthracycline-induced cardiotoxicity, a first necessary step to identify temporal correlations between physiological events that can support and motivate future clinical studies on patient cohorts. In Aim 1, we will relate the onset of cardiac injury with the progression of cardiac dysfunction and the evolution of aortic stiffness. Circulating levels of cardiac troponin I will be measured as a biomarker for myocardial damage, MR imaging of the left ventricular cavity combined with invasive central pressure measurements will be used to evaluate cardiac function from pressure/volume loops, and in vitro biaxial tests will be performed on isolated aortic specimens to estimate material, structural, and active stiffness. In Aim 2, progressive changes in stiffness will be related to the microstructural reorganization of the wall. Combining diverse biological assays (histology, immunohistochemistry, western blotting), we will quantify deposition and removal of collagen, cell migration, proliferation, and apoptosis, as well as the timeline for the inflammatory response that is expected to follow the production of reactive oxygen species associated with anthracycline treatment. Experimental data will inform a computational model for the growth and remodeling of the aorta that will identify the microstructural mechanisms responsible for aortic stiffening. Computational results will set the stage for mechanicistic studies designed to uncover the molecular pathways leading to the predicted microstructural reorganization.